Variant classification summary

NM_000518.5:c.20A>T

HBB · NP_000509.1:p.(Glu7Val) · NM_000518.5

GRCh37: chr11:5248232 T>A · GRCh38: chr11:5227002 T>A

Gene: HBB Transcript: NM_000518.5

Final call

VUS

PS1 strong PS3 supporting

Variant details

Gene

HBB

Transcript

NM_000518.5

Protein

NP_000509.1:p.(Glu7Val)

gnomAD AF

0.00265234532642101 (v4.1)

ClinVar

Pathogenic

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PS1 strong: c.20A>T is directly identified as the canonical HbS beta-Glu6Val change.

2

PS3 supporting: hemoglobin containing c.20A>T showed abnormal function, with isolated-variant attribution limited by the additional p.Leu68Phe change.

Final determination: Under generic ACMG/AMP 2015 fallback rules, one strong pathogenic criterion plus one supporting pathogenic criterion does not satisfy a listed pathogenic or likely pathogenic combination, and no benign rule is met; therefore the call is VUS.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	Not applicable: PVS1 requires a null variant (nonsense, frameshift, canonical splice, start-loss or stop-loss), and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Met	Met, strong: PMID:15470216 directly identifies c.20A>T as beta-Glu6Val, the standard HbS pathogenic amino-acid change.	PMID:15470216
PS2	Not met	Not met: c.20A>T was present in the father, whereas the reported de novo event was the different c.335C>T variant.	PMID:15470216
PS3	Met	Met, supporting: double-mutant hemoglobin containing c.20A>T had P50 43.0 versus 24.0 mm Hg for HbS with 3.0 mM DPG, but isolated-variant attribution is limited.	PMID:15470216
PS4	Not met	Not met: no verified affected-versus-control comparison or OR/RR >5.0 with a confidence interval excluding 1.0 was reported for this variant.	PMID:15470216 PMID:21045822 gnomad_v4
PM1	Not assessed	Not assessed: hotspot status is negative, but vcep_materials.json provides no approved HBB domain table for evaluating residue 7.	cspec
PM2	Not met	Not met: gnomAD v4.1 reports AF 0.00265 and 40 homozygotes, far above the PM2 threshold of 0.0001.	gnomad_v2 gnomad_v4
PM3	Not assessed	Not assessed: no affected-proband observation demonstrates c.20A>T in trans with a pathogenic variant and phase-confirming parental or offspring testing.
PM4	N/A	Not applicable: PM4 requires a protein-length change, and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: no verified pathogenic alternate missense change at HBB residue 7 is available for comparison with p.Glu7Val.
PM6	Not met	Not met: parental testing identified c.20A>T in the father, so the variant is inherited rather than assumed de novo.	PMID:15470216
PP1	Not assessed	Not assessed: no multiple affected relatives with documented c.20A>T carriage or quantified segregation data are available.
PP2	Not assessed	Not assessed: the case lacks gene-level evidence establishing both low benign missense variation and a common HBB missense disease mechanism.
PP3	Not met	Not met: REVEL 0.535 is below the generic PP3 supporting threshold of 0.644 for this missense variant.	revel
PP4	Not assessed	Not assessed: no patient phenotype or family history sufficiently specific for a single-genetic-etiology disease was documented.
PP5	Not met	Not met: ClinVar has no exact-variant expert-panel pathogenic assertion; its Pathogenic aggregate comes from ordinary laboratory submissions.	clinvar
BA1	Not met	Not met: the default gnomAD population maxima are 4.49% and 4.95%, both below the 5% BA1 threshold.	gnomad_v2 gnomad_v4
BS1	Not met	Not met: African-ancestry frequency reaches 4.95%, but HbS is a common malaria-selected recessive allele whose carrier frequency is expected for sickle-cell disease.	gnomad_v2 gnomad_v4 PMID:21045822
BS2	Not assessed	Not assessed: gnomAD reports 40 homozygotes, but it does not show that any homozygous individual was a healthy adult without sickle-cell disease.	gnomad_v2 gnomad_v4
BS3	Not met	Not met: functional testing showed abnormal oxygen binding and reduced solubility in hemoglobin containing c.20A>T, rather than a well-established absence of damaging effect.	PMID:15470216
BS4	Not assessed	Not assessed: no affected relative documented without c.20A>T, so qualifying lack-of-segregation evidence is absent.
BP1	Not met	Not met: PMID:15470216 documents the HBB missense beta-Glu6Val change as standard HbS with sickling disease.	PMID:15470216
BP2	Not assessed	Not assessed: c.20A>T is reported in cis with p.Leu68Phe, but that partner variant is not established as pathogenic in the available evidence.	PMID:15470216
BP3	N/A	Not applicable: BP3 requires an in-frame indel in a repeat region, and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: REVEL 0.535 exceeds the generic BP4 supporting upper threshold of 0.29 for this missense variant.	revel
BP5	Not assessed	Not assessed: no affected case with a documented alternate molecular basis explaining the disease was identified.
BP6	Not met	Not met: no exact-variant ClinVar expert-panel benign or likely-benign assertion was identified.	clinvar
BP7	N/A	Not applicable: BP7 requires a synonymous variant, and this is a missense variant.	generic_acmg_combination_rules

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.